chr11-64593747-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting

The NM_144585.4(SLC22A12):c.774G>A(p.Trp258*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000382 in 1,613,338 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00018 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00040 ( 6 hom. )

Consequence

SLC22A12
NM_144585.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.68

Variant links:

Genes affected

SLC22A12 (HGNC:17989): (solute carrier family 22 member 12) The protein encoded by this gene is a member of the organic anion transporter (OAT) family, and it acts as a urate transporter to regulate urate levels in blood. This protein is an integral membrane protein primarily found in epithelial cells of the proximal tubule of the kidney. An elevated level of serum urate, hyperuricemia, is associated with increased incidences of gout, and mutations in this gene cause renal hypouricemia type 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

SLC22A12 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-64593747-G-A is Pathogenic according to our data. Variant chr11-64593747-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000403 (589/1461002) while in subpopulation EAS AF= 0.0146 (581/39700). AF 95% confidence interval is 0.0136. There are 6 homozygotes in gnomad4_exome. There are 276 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A12	NM_144585.4 link	c.774G>A	p.Trp258*	stop_gained	Exon 4 of 10	ENST00000377574.6	NP_653186.2	Q96S37-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A12	ENST00000377574.6 link	c.774G>A	p.Trp258*	stop_gained	Exon 4 of 10	1	NM_144585.4	ENSP00000366797.1		Q96S37-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00520

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000283

AC:

AN:

250516

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00375

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000403

AC:

589

AN:

1461002

Hom.:

Cov.:

AF XY:

0.000380

AC XY:

276

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0146

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000177

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dalmatian hypouricemia

Pathogenic:6

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 21, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.026%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003512 / PMID: 12024214). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SLC22A12 c.774G>A (p.Trp258Ter) variant is a stop gained variant predicted to result in premature termination of the protein. The p.Trp258Ter variant is widely reported in the literature as the most common variant associated with renal hypouricemia in Japanese patients, and one of the most common variants in Korean renal hypouricemia patients. Across a selection of the available literature, the p.Trp258Ter variant has been reported in 79 of 91 Japanese and Korean patients, including in 42 individuals in a homozygous state, 24 individuals in a compound heterozygous state, and 13 individuals in a heterozygous state in whom a second variant was not detected (Enomoto et al. 2002; Tanaka et al. 2003; Komoda et al. 2004; Cheong et al. 2005; Komatsuda et al. 2006; Ichida et al. 2008). In a study of 909 subjects from the general Korean population, the p.Trp258Ter variant was observed in one compound heterozygote and 19 heterozygotes, seven of whom had hypouricemia, while a study of 5023 subjects from the general Japanese population reported the p.Trp258Ter variant in five homozygotes, all of whom had hypouricemia, and 225 heterozygotes (Lee et al. 2008; Hamajima et al. 2011). The variant was absent from 424 healthy controls in the above studies but is reported at a frequency of 0.02404 in the Japanese in Tokyo, Japan population of the 1000 Genome Project. This allele frequency is high but is consistent with the disease prevalence. Due to the potential impact of stop-gained variants and the supporting evidence from the literature, the p.Trp258Ter variant is classified as pathogenic for renal hypouricemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

SLC22A12-related disorder

Pathogenic:1

Jan 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SLC22A12 c.774G>A variant is predicted to result in premature protein termination (p.Trp258*). This variant is considered one of the most common variants associated with renal hypouricemia in individuals of Japanese and Korean descent (Taniguchi et al. 2005. PubMed ID: 16059895; Cheong et al. 2005. PubMed ID: 15912381). Functional studies showed defects in cellular localization and urate transport activity (Enomoto et al. 2002. PubMed ID: 12024214). This variant is reported in 0.36% of alleles in individuals of East Asian descent in gnomAD. Nonsense variants in SLC22A12 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Apr 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3512). This premature translational stop signal has been observed in individuals with renal hypouricemia (PMID: 19092327, 22257548, 23525542, 23652934). This variant is present in population databases (rs121907892, gnomAD 0.3%). This sequence change creates a premature translational stop signal (p.Trp258*) in the SLC22A12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC22A12 are known to be pathogenic (PMID: 14694169). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Pathogenic

0.97

Vest4

0.79

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over